PROJECT SUMMARY/ABSTRACT The risk of fracture, particularly hip fracture, among people with type 1 diabetes (T1D) is 3 to 6-fold higher than that of the general population. The increased risk of fracture starts as early as the first decade of life, suggesting that T1D affects bone development in childhood. This is not surprising: childhood and adolescence are critical periods for the development of the skeletal system, characterized by exuberant bone formation. Approximately 90% of the adult skeleton is formed by late adolescence; therefore, a process that interferes with bone formation in childhood has the potential to lead to profound and life-long effects. However, the specific insults to the skeleton that predispose patients with T1D to fracture and the mechanisms underlying these insults remain poorly understood. T1D-associated skeletal fragility is becoming an increasingly important public health problem. With a rising incidence of T1D in the population as well as improvements in life expectancy among patients with T1D due to improved treatment options, a larger number of T1D patients are aging and will be at risk for diabetes-associated fragility fracture, conferring substantial morbidity and mortality. The overall goal of this 2-year prospective observational study is to define the differences in bone development and the factors that cause these differences in children and young adults with T1D ages 6-20 years compared to their non-diabetic peers. Our preliminary data in pubertal girls demonstrate that trabecular bone density is low and trabecular bone morphology is altered in T1D, and that those children with higher average blood glucose as measured by HbA1c are more severely affected. In Aim 1, we will identify differences in bone mass, microarchitecture, and strength in both boys and girls across the age spectrum of childhood to young adulthood using second-generation high-resolution peripheral quantitative computed tomography. In Aim 2, we will determine which glycemic parameters predict altered bone mass, microarchitecture, and strength using continuous glucose monitoring to measure average glycemia, hyperglycemic time, and glucose variability. In Aim 3, we will use validated questionnaires assessing bone loading activities as well as accelerometry to determine to what extent the bone-forming response to physical activity is blunted in T1D. The Co-Principal Investigators, Drs. Deborah Mitchell, Madhusmita Misra, and Mary Bouxsein, have complementary clinical and research expertise in T1D, bone metabolism, and bone biomechanics. Data derived from this study will provide critical knowledge about the specific bone alterations in T1D and their underlying mechanisms to enable the development of targeted and effective therapies to prevent fragility fracture in this at-risk population.